An access to (Z)-ethylenic pseudodipeptides based on ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4020(02)00795-0

A new access to enantiopure (Z)-ethylenic pseudopeptides, starting from the chiral pool of amino acids and enantiopure 2-substituted-but-3-enoic acids is proposed and illustrated by the syntheses of the (Z)-ethylenic pseudopeptidic analogs of L-Phe-L-Phe, L-Phe-D-Phe, L-Phe-L-Val, L-Phe-D-Val and racemic (LL,DD) and (LD,DL) (phenyl)Gly-Phe. The key-steps of these syntheses are a ring-closing metathesis, catalysed by Grubbs' ruthenium alkykidene complexes, on diethylenic amides and the hydrolytic cleavage of the resulting dihydropyridones under mild conditions through intermediate formation of cyclic imidates.

Full text of DOI:10.1016/S0040-4020(02)00795-0

Tetrahedron 58 (2002) 7275–7290
An access to (Z )-ethylenic pseudodipeptides based on
ring-closing metathesis
*
´
´
´ `
Valerie Boucard, Helene Sauriat-Dorizon and Franc¸ois Guibe
´ ´ ´ ˆ
Laboratoire de Catalyse Moleculaire, Institut de Chimie Moleculaire d’Orsay, Universite Paris-Sud, UPRESA-8075, Bat 420,
91405 Orsay, France
Received 11 April 2002; revised 6 June 2002; accepted 28 June 2002
Abstract—A new access to enantiopure (Z)-ethylenic pseudopeptides, starting from the chiral pool of amino acids and enantiopure
2-substituted-but-3-enoic acids is proposed and illustrated by the syntheses of the (Z)-ethylenic pseudopeptidic analogs of L-Phe-L-Phe,
L-Phe-D-Phe, L-Phe-L-Val, L-Phe-D-Val and racemic (LL,DD) and (LD,DL) (phenyl)Gly-Phe. The key-steps of these syntheses are a ring-
closing metathesis, catalysed by Grubbs’ ruthenium alkykidene complexes, on diethylenic amides and the hydrolytic cleavage of the
resulting dihydropyridones under mild conditions through intermediate formation of cyclic imidates. q 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
N-terminal to these residues is greatly reduced (DH#2
kcal mol21)3 as compared to what is observed for other
proteinogenic amino acids (ca. 5 kcal mol21, see Fig. 1).4
The unique conformational properties of the Xaa-Pro link
play an important role in the structure and function of
peptides and proteins. In particular, cis-prolyl residues often
induce5 the formation of type VI b-turns, a special class of
reverse turn motifs in which they occupy the iþ2 position
among the four residues involved and which constitute a
basic recognition feature for peptide binding. Isomerisation
of Xaa-Pro epitopes and binding of proline are the principal
function of a vast and ubiquitously occurring group of
enzymes termed peptidyl-prolyl cis/trans isomerases
(PPPIases).6 PPIases are implicated in a wide array of
biologically important processes such as the folding of
nascent proteins, the modulation of immunosuppression, the
control of HIV infectivity or the regulation of calcium
release receptors.
Backbone modifications of peptides constitute an important
tool which may be directed towards several goals such as the
stabilisation of biologically active peptide against
enzymatic degradation, the development of peptidic hor-
mone analogs with agonistic or antagonistic properties, the
development of enzyme inhibitors or a better understanding
of structure–activity relationships.1 Among such modi-
fications, the isosteric replacement of the amide bond by a
carbon–carbon double bond is of special interest. Indeed, in
terms of bond length and bond angles, (E) and (Z)-olefinic
pseudopeptides are close, and at the same time con-
figurationally locked mimics of peptides with a trans and
cis-amide bond, respectively.2 Although thermodynami-
cally disfavoured compared to the trans ones, cis-amide
bonds are nevertheless encountered in naturally occurring
peptides, in particular in those which contain N-methyl
amino acids or proline residues because the energy gap
between the cis and trans forms of the amide bond
Given the importance of conformation effects on the
Figure 1.
Keywords: peptidomimetics; (Z-ethylenic)-pseudopeptides; (olefin) metathesis; ring-closing metathesis.
*
Corresponding author. Tel.: þ33-1-69-15-52-59; fax: þ33-1-69-15-46-80; e-mail: fraguibe@icmo.u-psud.fr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00795-0

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V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
Scheme 1.
biological activity of peptidyl prolylamides, it is not
surprising that much effort has been devoted to the obtention
of surrogates of cis- (and also trans ) Xaa-Pro units as well
as of cis-peptidic bonds in general. Thus, properly
substituted analogs of proline have been devised in order
to shift the cis–trans equilibrium of the amide bond in
favour either of the cis7 or the trans8 form. Conformation-
ally rigid surrogates of trans9 and cis prolylamides have also
been proposed.10 In particular, a number of Gly-Pro,
sometimes Xaa-Pro type VI b-turn peptidomimetics in the
form of functionalised azabicycloalkanes have been
described. Other rigid surrogates of the cis amide bond in
general include11 cyclocystine, 1,5-tetrazoles, 1,2-disubsti-
tuted pyrroles, o-aminomethylphenylacetic acid derivatives,
b-lactam derivatives and cyclic peptides but, to the best of
our knowledge, only very few examples of the utilisation of
the Z-alkene bond have been reported.†
tolerance towards a number of polar functional groups
including the amide function considerably increased the
scope of utilisation of olefin metathesis in synthetic organic
chemistry.15 This has led us to propose16a a convergent
approach to enantiopure (Z )-ethylenic pseudopeptides 4
whose key-steps are (Scheme 1) an intramolecular alkene
metathesis (ring-closing metathesis) on diethylenic amides
of general formula 2 followed by hydrolytic ring opening of
the dihydropyridone 3 thus formed. We already described,
in preliminary communications,16 the obtention of the
Z-ethylenic pseudopeptidic analogs of L-Phe-Gly and
L-Phe-L-Phe. We present here a detailed report of our
investigation which include the preparation of enantiopure
Z-alkene isosteres of L-Phe-L-Phe, L-Phe-D-Phe, L-Phe-L-
Val, L-Phe-D-Val and racemic R pR p and R pS p diastereo-
isomeric Z-alkene isosteres of (phenyl)Gly-Phe.
Rich and co-workers12 have prepared the (Z)-ethylenic
pseudopeptidic analog of [N-(methyl)-L-leucyl]-L-leucine
by alkylation with isobutyl iodide of [N-(methyl)-L-
leucyl]glycine. The reaction exhibits almost no diastereo-
selectivity but the two diastereoisomers were separated by
flash chromatography. Etzkorn and co-workers13 have
reported the stereoselective synthesis of the (Z)-alkene
isostere of L-Ala-cis-L-Pro, but the strategy used remains
limited to Xaa-Pro sequences. The synthesis of the (Z )-
alkenic analog of L-Pro-D, L-Phe was recently described by
Mann and co-workers14 and the two diastereoisomers were
also separated by chromatography.
2. Results and discussion
2.1. Preparation of bis-olefinic amides
The preparation of diethylenic amides 2 was planned
according to retrosynthetic Scheme 2. In anticipation of
the results concerning olefin metathesis, it should be noted,
that the presence of an auxiliary group Aux on the nitrogen
atom of dialkenic amides 2 is necessary for the RCM (ring-
closing metathesis) process to take place. Its role is probably
to ensure a sufficient proportion of the rotamer with a syn
orientation (as represented in 2) of the two ethylenic
appendages.
The devising, some years ago, by Schrock and Grubbs of
new ruthenium and molybdenum-based catalysts with high
The most obvious way to obtain dialkenic amides of general
structure 2 is by coupling 2-substituted but-3-enoic acids 5
with N-substituted allylamines 7. As to enantiopure
allylamines 8, many of them may be obtained in a
straightforward and well-documented way from the chiral
pool of aminoacids through reduction to the corresponding
aldehydes followed by Wittig olefination.17 However,
a-aminoaldehydes 10 are notoriously very prone to
racemisation.17 At the present time, only a limited number
of protecting groups on nitrogen are known to ensure
satisfactory configurational stability.18 None of these
protections on nitrogen is compatible with the coupling
reaction envisioned next. Therefore, our synthetic strategy
entails a transprotection at the allylamine stage as
represented in Scheme 2 (9!8!7).
†
By contrast, since the first report by Sammes and co-workers,2a several
strategies have been proposed for the obtention of E-ethylenic
isosteres.41a However, those which incorporate stereocontrol at both the
C(2) and the C(5) positions of the 5-amino-pent-3-enoic acid are still
relatively few and, as a rule, either lack generality and/or require many
steps. Hopkin’s convergent approach41b starts from independantly
prepared optically active aldehydes and sulfones and utilises the Julia–
Lythgoe reaction for construction of the double bond. In Procter’s
protocol41c the E-double bond is obtained through concerted fluoride ion-
induced desilylation and ring-opening of an appropriately and
stereoselectively substituted b-trimethylsilyl-g-lactone. Many recent
approaches utilise enantiopure allylic precursors on which repositioning
of the double-bond and enantioselective construction of the C(2) or the
C(5) chiral centres are achieved simultaneously. This can be done by way
of sigmatropic rearrangements including Claisen–Ireland,41d Claisen–
Johnson,41e
Still–Wittig41f,13
and
trichloroacetamidate41g,h
rearrangements, by way of anti-SN20 alkylation of allylic mesylates41i
or alkenyl aziridines41j with organocopper reagents or by way of
stereoselective electrophilic anti-hydroxymethylation,41k -nitration41l or -
aziridination41l of allylic silanes. However, the optically pure allylic
precursors which are needed in all these strategies are usually of difficult
or lengthy access.
For the obtention of (S)-1-benzyl-prop-2-enylamine from
L-phenylalanine and following the recommendation of
Albeck and Persky,19 the trityl group was chosen in
preference to the Boc group for temporary protection of

V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
7277
Scheme 2.
the nitrogen atom. Indeed, Wittig reaction on N-Boc-a-
aminoaldehydes are known to give poorly reproducible
results. N-trityl-(S )-1-benzyl-prop-2-enylamine 15 was
synthesised (Scheme 3) in 50% overall yield and in four
steps including reduction of L-phenylalanine to L-phenyl-
alaninol, N-tritylation, Swern oxidation and Wittig reaction.
N-trityl-(R )-1-benzyl-prop-2-enylamine ent-15 was
obtained in the same way from D-phenylalanine. The trityl
group was removed by HCl in aqueous acetone.19 The
enantiomeric purities (ee .98%) of (S)- and (R)-1-benzyl-
prop-2-enylamine 15 and ent-15 were checked on aliquots
by HPLC after N-tert-butoxycarbonylation.
alkylating agent, THF/HMPA, low temperature) was first
attempted, but in our hands this reaction gave very poor
results. On the contrary, alkylation of the enolate derived
from vinylacetic methyl ester22 was successsfully achieved
but difficulties were subsequently encountered in the
removal of the methyl ester group. A variety of conditions23
were investigated such as acidic hydrolysis in concentrated
hydrochloric acid, classical or hydrogen peroxide-assisted
saponification, iodotrimethylsilane- or boron trichloride-
induced demethylation, but in all cases partial or even total
reconjugation of the double bond to give crotonic acid
derivatives were observed. Replacement of the methyl
group by the more easily removable tert-butyl group was
then considered. However, the lithium enolate of tert-butyl
vinylacetate proved unreactive. Since the lithium enolate of
tert-butyl acetate is readily alkylated,24 this lack of
reactivity must be due to a cumulative effect of steric
hindrance brought about by the tert-butyl group and of
lowering of nucleophilicity due to charge delocalisation
across the vinylacetyl group. The alkylation reactions were
finally performed on the allyl ester of vinylacetic acid
(Scheme 5). An excess of allyl vinylacetate over the
Due to the high cost of enantiomerically pure phenyl-
glycine, 1-phenyl-prop-2-enylamine 19 was synthesised in
racemic form. It was obtained in 72% overall yield, starting
from cinnamic alcohol and by rearrangement of the
corresponding trichloracetimidate according to Overman
(Scheme 4).20
For the obtention of racemic a-substituted vinylacetic acids,
direct alkylation of the dianion of vinylacetic acid21 (LDA,
Scheme 3. (i): NaBH4, H2SO4/Et2O, 08C, then MeOH, NaOH 5N, rfx; (ii): TrtCl, Et3N, CH2Cl2, rt; (COCl)2, DMSO, Et3N, CH2Cl2, 2788C; (iv):
Ph3PCHþ3 Br2, n-BuLi, THF, 2788C; (v): HCl 32%, acetone, rfx.
Scheme 4. (i): HNa (10 mol%), CCl3CN, Et2O, 08C then rt; (ii) xylene, rfx, 14 h; (iii): NaOH 6N, EtOH, rt, 40 h.
Scheme 5. (i), (ii), (iii): see text.

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V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
Figure 2.
deprotonating agent (lithium diisopropylamide) had to be
used in order to avoid the concurrent formation of a,a-
dialkylated products. Alkylations with benzyl bromide and
isopropyl iodide gave, respectively, a-benzyl and a-iso-
propyl vinylacetic acid allyl esters 21 and 22 in 85 and 40%
yields (based on LDA). Deallylation under neutral con-
ditions was effected by resorting to catalytic p-allyl
palladium chemistry.25 Thus, a-benzyl and a-isopropyl
vinylacetic acids 23 and 24 were obtained, respectively, in
90 and 52% yield by exposure of the allyl esters to
phenylsilane as the allyl group scavenger and 0.5 mol% of
palladium (tetrakis)triphenylphosphine as the catalyst.26
Final conversion to acyl chlorides was achieved in 72%
(R¼Bn) and 61% (R¼i-Pr) yields by reaction with
dichloromethyl methyl ether.27
NaBH4 at room temperature in absolute EtOH to give the
N-ferrocenylmethylamine 33 in 86% overall yield from 15.
At this stage, we were disappointed to find that the
enantiomeric purity of 33 (measured on an aliquot after
trifluoroacetolytic deprotection followed by tert-butoxycar-
bonylation) had dropped to 62%. Suspecting that this partial
racemisation had occurred at the imine stage under the basic
conditions of its formation and/or reduction with NaBH4,
we tried to obtain 33 according to a one-pot reductive
alkylation procedure. (1S)-1-amino-1-benzyl-prop-2-ene 15
was reacted with ferrocenecarboxaldehyde in the presence
of acetic acid and sodium cyanoborohydride or of sodium
triacetoxyborohydride in methanol. Unfortunately, and for
reasons which we have not elucidated, no formation of
N-Fcm derivative 33 was observed under such conditions.‡
(R )-2-benzyl-but-3-enoic acid and (R)-2-isopropyl-but-3-
enoic acid were prepared according to Oppolzer,28 by
regioselective and diastereoselective (de .99% as checked
by HPLC) alkylation of the (1S )-(2)-2,10-camphor-sultam
derivative of vinylacetic acid 27 with benzyl bromide (62%
yield) or isopropyl iodide (43% yield) followed by hydrogen
peroxide-mediated saponification29 of the alkylation
adducts 28 and 29 (Fig. 2). Fortunately, no reconjugation
of the double bond was observed during this process. The
carboxylic acids were finally reacted with dichloromethyl
methyl ether to give (R )-2-benzyl-but-3-enoyl chloride 30
and (R )-2-isopropyl-but-3-enoyl chloride 31 in, respect-
ively, 80£72¼58% and 51£70¼36% yields from inter-
mediates 28 and 29. Their enantiomeric purities (ee.98%)
were checked after recondensation with (1R)-(þ)-2,10-
camphor-sultam and examination of the diastereomeric
purity of the adduct. In order to verify that no significant
kinetic resolution ocurred in this reaction, a control
experiment was carried out in which racemic (R,S )-2-
benzyl-but-3-enoyl chloride was reacted with a limited
amount (0.5 equiv.) of (1S)-(2)-bornane-10,2-sultam. This
reaction was found to lead to an equimolecular mixture of
the two diastereoisomeric sulfonimides.
Another possible candidate was the benzenesulfonyl group,
easy to introduce by N-sulfonylation and whose cleavage23
from nitrogen especially under reductive conditions (SmI2,
etc.) has been described in several papers.31 However, we
found that condensation between N-sulfonylallylamines and
vinylacetyl chlorides bearing a-substituents invariably
resulted, under a variety of conditions, in low yields and
extensive reconjugation of the double bond of the
vinylacetyl moiety.
The 2,4-dimethoxybenzyl (Dmb) group was finally selected.
Probably as a result of the presence of the methoxy group at
the ortho position of the phenyl ring,32 acylation of N-Dmb
derivatives of amino acids or amines in general has been
shown to remain relatively easy (as compared to the
corresponding unsubstituted N-benzyl derivatives). Con-
densation of 2,4-dimethoxybenzaldehyde with racemic
1-phenyl-prop-2-enylamine 19 in the presence of sodium
triacetoxyborohydride in 1,2-dichloroethane33 afforded the
N-Dmb adduct 34 (Fig. 3) in 78% yield. N-trityl-(S)-1-
benzyl-prop-2-enylamine 14 was detritylated in HCl/
aqueous acetone19 at reflux and directly reacted, without
intermediate purification, with 2,4-dimethoxybenzalde-
hyde/sodium triacetoxyborohydride as before to lead to
N-Dmb-(S )-1-benzyl-prop-2-enylamine 35 in 61% overall
yield and without any racemisation. N-Dmb-(R )-1-benzyl-
prop-2-enylamine ent-35 was obtained in the same manner.
Concerning the auxiliary group on nitrogen, several groups
were considered. In the first stage of our investigations
dealing with the synthesis of the (Z )-ethylenic pseudo-
peptidic analog of L-Phe-Gly,16a the ferrocenylmethyl
(Fcm) group had been selected. Indeed, unlike many other
N-substituted aminoacids, N-Fcm derivatives of aminoacids
have been described as reactive in conventional (DCC/
DMAP) peptidic coupling reactions.30 (S )-1-benzyl-prop-2-
enylamine 15 was converted to ferrocenylimine 32 by
reaction for 6 h at room temperature with ferrocenecarbox-
aldehyde in dichloromethane and in the presence of
molecular sieves. The crude imine was reduced with
Acylation of 35 with (R )-2-benzyl-but-3-enoyl chloride 30
‡
We are not aware of any examples in the litterature of direct conversion of
ferrocecarboxaldehyde to ferrocenylamine through one-pot reductive
amination with borohydrides. Eckert and Deidel30 used dihydrogen gas in
the presence of palladium catalyst to effect the reduction of
ferrocenylimines to ferrocenylamines, a method that could not be
applied to our case due to the presence of ethylenic bonds.

V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
7279
Figure 3.
(80% yield), 36b (59% yied) and 37b (59% yield) were
similarly obtained, in all cases with the same purity, by
condensation of 35 or its enantiomer ent-35 with (R )-2-
benzyl-but-3-enoyl chloride 30 or (R)-2-isopropyl-but-3-
enoyl chloride 31. Coupling of racemic N-Dmb-1-phenyl-
prop-2-enylamine 34 with racemic acyl chlorides 25 and 26
gave the corresponding amides, respectively, in 82 and 52%
yield and as a ca. 1:1 mixture of diastereoisomers 38a/38b
and 39a/39b which could not be separated by chromato-
graphy. For all amides 36–39 NMR showed the presence of
two rotamers, but, due to peak overlapping, only in the case
of 36a and 36b could their relative proportions (ca. 4:1) be
properly estimated.
Figure 4.
under standard conditions (Et3N, dichloromethane, 08C then
room temperature) gave poor results. 36% of the expected
amide 36 was obtained, but contaminated with a side-
product whose structure was not elucidated. Fortunately, by
resorting to BSA-mediated acylation as described by
Raucher and Jones,34 satisfactory results were finally
obtained and 36a was isolated in 90% yield, with no
detectable reconjugation of the double bond and in
diasteroisomerically and enantiomerically pure form (de,
ee.98%), as determined by chiral HPLC. Amides 37a
2.2. Ring-closing metathesis of N-Dmb-bis-olefinic
amides to N-Dmb-dihydropyridones
RCM of bis-olefinic amides to the corresponding N-2,4-
dimethoxybenzyl-dihydropyridones were carried out in
benzene at 608C at a 0.03 M concentration and with 10–
20 mol% of Grubbs’ first or second generation catalysts 40
or 41 (Fig. 4).
Table 1.
Catalyst (amount)
Reaction time (h)
Total yield (%)a
42a/42bb
2:1
3:2
40 (10 mol%þ10 mol% after 12 h)
40 (4 mol%£4 every 6 h)
41 (10 mol%)
30
24
24
76
84
94
1:1
a
Isolated yield (column chromatography).
42a and 42b were separately collected by chromatography.
b

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V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
Table 2. Ring-closing metathesis of bis-olefinic amides
Starting amides
Dihydrophridones
Yield (%)a,b
84
72
90
83
90
80
a
After purification by chromatography.
Reaction conditions: benzene solution 0.03 M in substrate, 41 (10 mol%), 608C, 24–36 h.
b
The results reported in Table 1 concerns RCM of the
diastereomeric mixture 38aþ38b. They show that, as it is
generally the case,15a,b catalyst 41 proved more efficient
than catalyst 40. Due to its comparatively greater fragility,
catalyst 40 had to be added in several portions to
improve the yields. Even so, those remain lower than the
94% yield obtained with catalyst 41. The diastereoisomeric
N-Dmb-dihydropyridones 42a and 42b were separated by
column chromatography and their respective relative
stereochemistry (R pS p and R pR p) could later be

V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
7281
Scheme 6.
established by NMR studies on the corresponding
N-deprotected dihydropyridones in racemic liquid crystal-
line solvent.§ The results of Table 1 show that RCM of the
R pS p amide 38a leading to (R pS p) cis cyclised product 42a
occurs more readily than RCM of diastereoisomeric R pR p
amide 38b to the (R pR p) trans cyclic isomer 42b. The
reason for this difference in reactivity is not clearly
understood.
2.3. Removal of Dmb group and hydrolysis of
dihydropyridones to Z-ethylenic pseudodipeptides
Final conversion of N-Dmb pyridones to Z-ethylenic
pseudopeptides was carried out as illustrated for the case
of the (2R,6S)-dibenzylsubstituted compounds in Scheme 6.
Removal of the Dmb group from diastereoisomerically and
enantiomerically pure 44a, 44b, 45a, 45b and diastereo-
isomerically pure but racemic 42a and 42b{ was achieved in
80–88% yield in dependance of the substitution pattern of
the dihydropyridone by treatment with anhydrous trifluoro-
acetic acid35 in the presence of triethylsilane for carbocation
scavenging. Due to the harsh conditions it requires, direct
hydrolytic ring opening of the N-deprotected dihydro-
pyridones proved unsatisfactory. Therefore, dihydropyri-
dones were first converted to imidates by reaction with
triethyloxonium tetrafluoroborate in dichloromethane at
room temperature and under an argon atmosphere. Tetra-
fluoroboric acid and triethyloxonium tetrafluoroborate in
excess were eliminated by extraction of the organic phase
with pH 7 phosphate buffer. After drying and evaporation,
crude imidates were obtained, contaminated (NMR in dry
CD2Cl2) by a small amount (less than 10%) of starting
dihydropyridones.k They were directly hydrolysed to
aminoester at room temperature under mild acidic con-
The results concerning RCM of all N-Dmb-amides using
10 mol% of catalyst 41 are summarised in Table 2. Yields in
cyclised products (from 72 to 94%) are quite satisfactory,
given that both olefinic bonds taking part in the metathesis
process bear rather bulky groups at the allylic position. In
the enantioenriched series, (S,R) amides 36a, 37a and (R,R )
amides 36b and 37b were found to lead, respectively, and
exclusively (by NMR standards) to (3R,6S) 44a, 45a and
(3R,6R ) dihydropyridones 44b, 45b, showing the enantio-
conservative character of the metathesis reaction. Unlike
42a and 42b, the diastereoisomeric N-Dmb-dihydro-
pyridones 43a and 43b obtained from RCM of the
diastereoisomeric mixture of (R pR p) and (R pS p) amides
39a and 39b could not be separated by column
chromatography.
ditions (0.3 M HCl in water/ethanol) similar to those used
36,37
¨
by Schollkopf for cleavage of cyclic bis-lactim ethers.
§
An equimolecular mixture of poly-g-benzyl-L-glutamate (PBLG) and
We previously reported16a that the hydrolytic ring opening
of the imidate derived from 6-benzyl-2,6-dihydropyridone
(i.e. with no substituent on the carbon next to carbonyl) was
followed by a slow (6 days) but complete hydrolysis of the
aminoester to acid and this unexpected reaction had been
tentatively explained by a general acid catalysis by the
neighbouring NHþ3 group. Disubstituted aminoesters how-
ever did not display such unusual sensitivity to acidic
medium and conversions to amino acids had finally to be
achieved under standard conditions in refluxing 6N HCl for
poly-g-benzyl-D-glutamate (PBDG) in CDCl3 was used in this study (see
for instance Canlet, C.; Merlet, D.; Lesot, P.; Meddour, A.; Loewenstein,
A.; Courtieu, J. Tetrahedron: Asymmetry 2000, 11, 1–5). The assignment
of the relative stereochemistry at C(3) and C(6) for 42a and 42b is based
on the measurement of the carbon–proton residual dipolar couplings DCH
of the heterocycle and subsequently on the calculation of ordering tensor
for this part of the molecule, assuming a model geometry for the two
diastereoisomers (Boucard, V., Aroulanda, C.; Merlet, D, to be published
eslsewhere). Shortly: due to the planearity of the ethylenic and the amide
bonds, 42a and 42b adopt a butterfly-like shape. Given the rapid
equilibrium between the two possible conformers on the NMR time scale,
the C(3)–H and C(6)–H bonds may be considered as almost anti-parallel
in the (R p,R p) (trans) diasteroisomer but have different orientations in
the (R p,S p) (cis ) isomer. Therefore, in the first case similar, and in the
second case different dipolar coupling constants are expected in an
anisotropic medium. Compound 42b, the first one to be eluted during
column chromatography, exhibits the same value of þ87 Hz for the two
dipolar coupling constants DC(3)–H and DC(6)–H. On the contrary,
compound 42a exhibits very different dipolar coupling constants:
DC(3)–H¼265 Hz and DC(6)–H¼þ97 Hz. The (R p,S p) and (R p,R p)
configurations may thus confidently be assigned, respectively, to 42a and
42b.
Conversion to Z-ethylenic pseudopeptides of (3R p,6S p) 43a and
(3R p,6R p) 43b which could not be separated by chromatography was
not undertaken.
This small amount of dihydropyridone is more likely the result of a partial
rehydrolysis of the imidate ester during work-up than that of an
uncomplete reaction with triethyloxonium tetrafluoroborate. Indeed
under non acidic conditions imidate esters are known to be hydrolysed
back to amides (Patai, S. Chemistry of the Amidines and the Imidates;
John Wiley: NY, 1975; Vol. 1, Chapter 9, p 423).
{
k

7282
Table 3. Conversion of N-Dmb-dihydropyridones to Z-ethylenic pseudopeptides
N-Dmb-digydropyridones Z-ethylenic pseudopeptides
V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
Overall yields
A (%)a B (%)b
Corresponding aminoacid sequence
42a (rac)
(Phenyl)Gly-Phe (LLþDD)
60
47
42b (rac)
(Phenyl)Gly-Phe (LDþDL)
71
55
44a
44b
45a
72
67
66
65
53
45
40
30
L-Phe-L-Phe
D-Phe-L-Phe
L-Phe-L-Val
D-Phe-L-Val
45b
a
From N-Dmb-dihydropyridone (four steps).
From N-Dmb-allylic amines (six steps).
b
one to three hours. The crude aminoacids were purified by
ion-exchange chromatography. They were obtained
diastereoisomerically pure by NMR standard (de .95%).
Overall yields from N-Dmb-dihydro-pyridones (60–76%)
and from N-Dmb-amines (35–60%) are summarised in
Table 3.
be converted to otherwise difficult to obtained enantiopure
Z-ethylenic pseudopeptides. We are now working at the
incorporation of such entities in short polypeptidic units.
Aside from their own interest, Z-ethylenic isosteres are
likely to be, by use of one of the many methods available for
olefin inversion,38 direct precursors of their E-congeners
whose access, as already pointed out in footnote† of the
introduction is rather difficult, and of various potentially
interesting polyfunctional pseudopeptidic entities through
stereospecific transformations of the double bond such as
epoxidation, aziridination or dihydroxylation. These are
under current investigation.
3. Conclusion
In conclusion, ring-closing metathesis of easily accessible
enantiopure bis-olefinic amides leads, in good to excellent
yields to dihydropyridones which in turn may in few steps

V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
7283
4. Experimental
(broad q, 1H, CH a to CvO); 3.82–3.75 (m, 1H, CH a to
N); 3.42–3.29 (dd, AB system, 2JAB¼14 Hz, 2H, CH2 a to
SO2); 3.18–3.08 and 2.92–2.82 (two dd, AB X system,
Typical experimental procedures are given for the synthesis
of the (Z )-alkene pseudopeptidic analog of L-Phe-L-Phe.
Unless otherwise mentioned, similar protocols have been
used in the synthesis of other pseudopeptidic analogs. The
experimental procedures for the preparation of enantio-
merically pure (R ) and (S )-1-benzyl-prop-2-enylamine
from D- and L- phenylalanine are essentially those of
Albeck and Persky19 and are not described here. Reduction
of phenylalanine to phenylalaninol (step (i) in Scheme 3)
was carried out according to Abiko and Masamune.39 The
preparation of racemic 1-phenyl-prop-2-enylamine from
cinnamyl alcohol by the trichloroacetamidate method has
been described by Overman.20
2JAB¼12 Hz, JAX¼8 Hz, JBX¼5 Hz, (1þ1)H); 2.0–1.65
m, 5H); 1.38–1.22 (m, 2H); 0.87 (s, 3H); 0.63 (s, 3H). 13C
NMR: d 172.5; 137.7; 134.7; 129.5; 128.2; 127.8; 126.5;
118.5; 65.15; 53.07; 51.35; 44.6; 40.1; 38.25; 32.8; 26.35;
3
3
20.4; 19.8. IR (CHCl3): 1691 (CvO); 1639 (CvC) cm21
.
GC/MS (EI) m/z: (rel. int.): 282 [Mþ] (0.5%), 159 (20%),
131 (55%), 91 (100%). Anal. Calcd for C21H27NO3S: C,
67.56; H, 7.24; N, 3.75; S, 8.58. Found: C, 67.27; H, 7.21;
N, 3.73; S, 8.59.
4.1.2. N-[(2R )-2-Isopropyl-3-butenoyl]-(1S )-2,10-cam-
phorsultam 29. Yield 43%. White crystals. Mp: 152–
1538C. [a ]2D0¼295.9 (c 1, CHCl3). 1H NMR (250 MHz): d
5.90–5.66 (m, 1H); 5.3–5.1 (m, 2H); 3.9–3.8 (t, 1H,
3J¼5.5 Hz, CH a to CvO); 3.55–3.38 (dd, AB system, 2H,
2J¼13.5 Hz, CH2 a to SO2); 3.39–3.29 (t, 1H, 3J¼8 Hz, CH
a to N); 2.15–2.0 (m, 3H); 1.95–1.80 (m, 3H); 1.45–1.28
(m, 2H); 1.16 (s, 3H); 0.97–0.85 (m (two dþone s), 9H).
13C NMR: d 172.5; 137.7; 134.3; 118.8; 65.4; 53.15; 50.5;
118.15; 44.6; 32.5; 32.8; 32.4; 26.3; 20.7; 20.4; 19.8; 19.45.
4.1. General information
Melting points are uncorrected. 1H NMR spectra were
recorded at 200 or 250 MHz and 13C NMR spectra at
63 MHz. CDCl3 was used as solvent if not mentioned
otherwise. Chemical shifts are quoted in ppm relative to
TMS. When necessary, unambiguous 1H NMR assignments
were obtained by decoupling or COSY experiments.
GC/MS analyses were carried out on a OK1 DP 125 gas
chromatograph equipped with a CPSil quartz capillary
column and connected to a Riber Mag R10-10 mass
detector. High resolution mass spectra (HRMS) and
electrospray mass spectra were obtained on a Finningan-
MAT-95-S spectrometer. HPLC analyses were performed
on a Spectra-Physics P100-UV100 HPLC system with
detection at l¼254 nm and equipped with a chiral column
Chiralcel OD-H from Daicel Chemical Industries Ltd.
Mixtures of hexane and isopropanol were used for elution.
Optical rotations were measured with a Perkin–Elmer 241
polarimeter at room temperature (concentration in
g/100 mL). All solvents were dried and freshly distilled
under a nitrogen atmosphere. If not otherwise stated,
reactions were performed under argon atmosphere using
standard Schlenk techniques.
4.1.3. (2R )-2-Benzyl-3-butenoic acid. To a solution of
2.20 g (5.93 mmol) of 28 in a mixture of 40 mL of THF and
10 mL of water were successively added 1 g (23.7 mmol) of
LiOH·H2O and 4.15 mL (47.40 mmol) of 35% aqueous
hydrogen peroxide. The reaction mixture was stirred first for
1 h at 08C and then overnight at room temperature. After
acidification to ca. pH 2 with 2N hydrochloric acid, the
aqueous phase was extracted several times with CH2Cl2.
The combined organic phases were washed with brine, dried
over MgSO4 and concentrated by rotary evaporation. The
residue was taken up in hexane and the resulting
heterogeneous mixture was filtered. The precipitate was
washed with hexane and discarded. Evaporation of the
filtrates gave 1.12 g of crude acid as an oil contaminated
with small amounts (,10%) of camphorsultam-derived by-
products. Yield: ca. 90%. Oil. 1H NMR (200 MHz): d 11.65
(broad s, 1H); 7.38–7.18 (m, 5H, Ar–H); 5.98–5.80 (m,
3
4.1.1. N-[(2R )-2-Benzyl-3-butenoyl]-(1S )-2,10-camphor-
sultam 28. To a solution in 30 mL of THF cooled at 2788C
of 6.32 g (22.3 mmol) of (1S,5R )-N-but-3-enoyl-2,10-
camphorsultam (prepared by acylation of the sodium salt
of (1S,5R)-(2)-2,10-camphorsultam with 3-butenoyl
chloride in toluene according to published procedures40)
was added dropwise through a cannula and over a period of
ca. 1 h a solution of 4.1 g of sodium hexamethyldisilazane
(22.3 mmol) in 80 mL of THF. The solution, which became
orange-coloured, was stirred for 1 h at 2 788C. 8 mL
(66.9 mmol) of benzyl bromide diluted in 9.3 mL
(66.9 mmol) of HMPA was then slowly added. The reaction
mixture was stirred for 16 h at 2408C, upon which it was
warmed above 08C and quenched with 200 mL of water.
The aqueous mixture was extracted several times with
AcOEt. The organic phases were combined, washed with
brine, dried over MgSO4, filtered and concentrated by rotary
evaporation. The residual solid was recrystallised in MeOH
to afford 5.16 g of 28 as white crystals. Yield: 62%. Mp:
167–1688C. [a]2D0¼247 (c 1, CHCl3). 1H NMR
(250 MHz): d 7.25–7.1 (m, 5H, Ar–H); 6.0–5.85 (m, 1H,
vinylic CH); 5.25–5.12 (m, 2H, vinylic CH2); 4.1–4.0
1H, vinylic CH); 5.20 (d, Jcis¼10 Hz, 1H, vinylic CH H);
3
5.14 (d, Jtrans¼17.3 Hz; 1H, vinylic CHH ); 3.46–3.3
(broad q, J¼7.6 Hz, 1H, CH a to CvO); 3.15–3.10 and
2.9–2.78 (two dd, ABX system, 2JAB¼13.5 Hz,
3
3JAX¼7.5 Hz, JBX¼7.5 Hz, (1þ1)H). 13C NMR: d 179.6;
138.15; 134.55; 128.25; 128.1; 126.4; 118.15; 51.7; 37.9. IR
(CCl4): 3525–3065 (OH); 1708 (CvO); 1639 (CvC)
cm21. GC/MS (EI) m/z: (rel. int.): 176 (Mþ), 91 (100%).
4.1.4. (2R )-2-Isopropyl-3-butenoic acid. The crude pro-
duct is distilled under reduced pressure. Bp: 1258C (1 mm).
Oil. Yield 51%. 1H NMR (250 MHz): d 11.4 (broad s, 1H);
5.9–5.67 (m, 1H); 5.18–5.1 (m, 2H); 2.78–2.62 (broad t,
3J¼ca. 11 Hz, 1H); 2.07–1.87 (m, 1H); 0.94 (d, 3J¼8.5 Hz,
3
3H); 0.88 (d, J¼8.5 Hz, 3H). 13C NMR: d 180.4; 134.4;
128.65; 57.9; 30.4; 20.6; 19.5.
4.1.5. (2R )-2-Benzyl-3-butenoyl chloride 30. A solution of
1 g (5.68 mmol) of crude (2R )-2-benzyl-3-butenoic acid
and 780 mL (8.60 mmol, 1.5 equiv.) of dichloromethyl
methyl ether in 12 mL of dichloromethane was heated at
reflux for 1 h. The solvent was evaporated and the residue

7284
V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
was purified by distillation to give 0.79 g of a colourless oil.
1
51.9; 38.3. GC/MS (EI) 216 (Mþ), 175 (M241, 100%), 129
(98%), 115 (33%), 91 (88%).
Bp: 1108C (1 mm). Yield 72%. H NMR (250 MHz): d
3
7.35–7.1 (m, 5H); 5.9–5.7 (m, 1H); 5.28 (d, Jcis¼10 Hz,
3
3
1H); 5.20 (d, Jtrans¼15 Hz, 1H); 3.7 (q, J¼8 Hz); 3.25–
4.1.9. Racemic 2-isopropyl-3-butenoic acid allyl ester 22.
Same experimental procedure as above, except that 2 equiv.
(based on n-BuLi) of alkylating agent (isopropyl iodide)
2
3.12 and 2.98–2.87 (two dd, ABX system, JAB¼14 Hz,
3
3JAX¼7.5 Hz, JBX¼7.5 Hz, (1þ1)H). 13C NMR: d 179.6;
1
138.1; 134.5; 128.25; 128.1; 126.4; 118.15; 51.7; 37.9. IR
(CCl4): 1792 (CvO); 1638 (CvC) cm21. GC/MS m/z: (rel.
int.): 159 [Mþ2Cl], 131 (10%), 91 (100%).
was used. Yield: 46%. H NMR (250 MHz): d 5.97–5.72
(m, 2H); 5.32–5.05 (m, 4H); 4.51 (d, 3J¼5.5 Hz, 2H);
3
3
2.75–2.63 (t, J¼9 Hz, 2H); 2.1–1.9 (broad oct, J¼ca.
3
3
7 Hz, 1H); 0.90 (d, J¼7 Hz, 3H); 0.86 (d, J¼7 Hz, 3H).
13C NMR: d 173.45; 135.0; 132.2; 64.95; 58.15; 30.60;
20.7; 19.6.
4.1.6. 2R-2-Isopropyl-3-butenoyl chloride 31. The
dichloromethane solution of the acid and dichloromethyl
methyl ether was refluxed during 16 h. The solvent was then
evaporated and the crude acyl chloride (yield 70%) was
directly engaged in coupling reactions with the N-Dmb
4.2. Racemic 2-benzyl-3-butenoic and racemic 2-iso-
propyl-3-butenoic acids 23 and 24
1
allylic amines. Oil. H NMR (200 MHz): d 5.9–5.7 (m,
3
1H); 5.35–5.18 (two overlapping d (app. t), Jcis¼10 Hz,
In a Schlenk tube under an argon atmosphere 1 g (4.6 mmol)
of 2-benzyl-3-butenoic acid allyl ester 21 was dissolved in
10 mL of degassed dichloromethane. 1.14 mL (9.2 mmol)
of phenylsilane was then syringed into the solution followed
by 26.5 mg (0.023 mmol) of palladium tetrakis(triphenyl-
phosphine) rapidly added as a solid. A mildly exothermic
reaction with gas evolution immediately ensued. After
30 min, the golden-yellow solution was twice treated for a
few minutes with 10 mL of half-saturated aqueous HCO3Na
under vigorous stirring. The aqueous phases were then
acidified with aqueous HCl and twice extracted with
dichloromethane. The organic phase was dried over
MgSO4 and evaporated to give 688 mg of racemic
2-benzyl-3-butenoic 23 as a colourless oil.
3
3Jtrans¼18 Hz, 2H); 2.78–2.65 (broad t, J¼ca. 8–9 Hz,
3
1H); 2.12–1.88 (broad oct. J¼ca. 6–7 Hz, 1H); 1.01 (d,
3J¼6.5 Hz, 3H); 0.89 (d, 3J¼6.5 Hz, 3H). 13C NMR: d
207.1; 132.1; 121.1; 68.6; 30.6; 20.2; 19.0. IR (CCl4): 1792
.
(CvO); 1639 (CvC) cm21
4.1.7. But-3-enoic acid allyl ester 20. 16 g (0.186 mol) of
vinylacetic acid and 38 mL (0.56 mol) of allyl alcohol were
diluted in 100 mL of benzene. To this solution were added
10.66 g (0.056 mol) of p-toluene sulfonic acid monohydrate
and the reaction mixture was refluxed for about 3 h with
azeotropic elimination of water in a Dean–Stark separator.
The reaction mixture was extracted with aqueous HCO3Na
and dried with MgSO4. Benzene was eliminated through a
Vigreux column at atmospheric pressure and the residue
was distilled to give 13.8 g of 20 as a colourless liquid. Bp:
1258C (760 mm). Yield: 60%. 1H NMR (200 MHz): d
5.93–5.71 (m, 2H); 5.25–5.0 (m, 4H); 4.50–4.47 (d,
3J¼5 Hz); 3.02 (d, 3J¼7 Hz, 2H). 13C NMR: d 171.0; 131.9;
130.05; 121.1; 65.2; 38.9.
By the same procedure racemic 2-isopropyl-3-butenoic acid
24 was obtained from allyl ester 22.
4.2.1. 1-[N-(10S)-(10-Benzyl-prop-20-enyl)amino]methyl-
2,4-dimethoxybenzene 35. 870.4 mg (2 mmol) of
NaBH(OAc)3 were added, as a solid, to a solution of
588 mg (2 mmol) of (S)-1-benzyl-prop-2-enylamine 15 and
680 mg (2 mmol) of 2,4-dimethoxybenzaldehyde in 200 mL
of dichloroethane. The reaction mixture was stirred at room
temperature for 16 h and then quenched with saturated
aqueous Na2CO3. The organic phase was washed with brine
and dried over MgSO4. After evaporation, the residue was
purified by column chromatography on silica gel (eluent
heptane/AcOEt from 6:4 to 2:8 with 1% Et3N). Yield
4.1.8. Racemic 2-benzyl-3-butenoic acid allyl ester 21.
3.72 mL of a 1.6 M solution of n-BuLi in hexane were
added at 08C to a solution of 834 mL (5.94 mmol) of dry
diisopropylamine in 4.5 mL of THF. After 30 min, the
solution was cooled to 2788C and 1.07 mL of HMPA
(6.15 mmol) were added to it. The reaction mixture was
stirred at 2788C for 1 h. 3 g (23.8 mmol) of 3-butenoic acid
allyl ester diluted in 4.5 mL of THF were then added
dropwise over a period of 30 min. The reaction mixture was
stirred at 2788C for 1 h, upon which 0.71 mL of benzyl
bromide (5.95 mmol) were added over a few minutes.
Stirring at 2788C was continued for 1 h before quenching
the reaction mixture by 10 mL of 5% aqueous HCl. The
aqueous phase was extracted several times with ether and
the organic phase was washed with 5% aqueous HCl and with
brine and dried over MgSO4. After evaporation, the residue
was purified by column chromatography (silicagel, eluent
heptane/AcOEt 95: 5) to give 1.06 g of 21 as a colourless oil.
Yield (based on n-BuLi): 82%. 1H NMR (250 MHz): d 7.30–
7.10 (m, 5H, Ar–H); 5.83–5.7 (m, 2H, two vinylic CH); 5.3–
5.05 (m, 4H, two vinylic CH2); 4.51 (d, 3J¼5.5 Hz, 2H, CH2 a
to O); 3.42–3.28 (q, 3J¼7.5 Hz, 1H, CH2 a to CvO); 3.17–
725 mg (61%). [a]2D0¼224.2 (c 1.75, CHCl3). H NMR
1
(250 MHz): d 7.3–7.08 (5H, benzyl Ar–H); 6.95 (d,
3J¼8 Hz, 1H, Dmb Ar–H); 6.4–6.3 (m, 2H, Dmb Ar–H);
5.85–5.62 (m, 1H); 5.18–5.02 (m, 2H); 3.75 (s, 3H); 3.47
2
(s, 3H); 3.66 and 3.46 (two d, AB system, JAB¼13 Hz,
(1þ1)H); 3.27–3.17 (m, 1H, CH a to N); 2.82–2.72 and
2.71–2.60 (two dd, AB X system 2JAB¼13 Hz, 3JAX¼5 Hz,
3JBX¼9 Hz, (1þ1)H). 13C NMR: d 159.75; 158.5; 141.0;
138.5; 130.25; 129.15; 128.1; 126.0; 120.25; 115.95;
103.05; 98.1; 61.2; 55.1; 54.6; 46.7; 42.3. GC/MS m/z:
(rel. int.): 297 [Mþ], 151 (100%, Mþ2C6H3(MeO)22CH2);
206 (60%), 91 (35%). HRMS (EI) calcd for C19H23NO2
[Mþ] 297.1728, found 297.1727.
4.2.2. 1-[N-(10R)-(10-Benzyl-prop-20-enyl)amino]methyl-
2,4-dimethoxybenzene ent-35 and racemic 1-[N-(10-
phenyl-prop-20-enyl)amino]methyl-2,4-dimethoxyben-
zene 34. Yields around 80% were obtained by the same
2
3.05 and 2.90–2.78 (two dd, AB X system, JAB¼13.5 Hz,
3
3JAX¼7.5 Hz, JBX¼7.5 Hz, (1þ1)H). 13C NMR: d 172.75;
138.4; 135.2; 131.8; 128.9; 128.2; 126.3; 118.0; 117.6; 65.05;

V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
7285
procedure. 1-[N-(10-phenyl-prop-20-enyl)amino]methyl-2,4-
4.2.5. (2R,10S )-N-(10-Benzyl-prop-20-enyl)-N-[2,4-
dimethoxyphenyl)methyl]-2-isopropyl-but-3-enamide
37a. Pale yellow oil. Yield 60%. [a ]2D0¼291.2. (c 1.0,
CHCl3). 1H NMR (250 MHz): d 7.30–6.95 (m, 6H, benzyl
Ar–Hþ1 Dmb Ar–H); 6.45–6.35 (m, 2H, Dmb Ar–H);
5.98–5.78 (m, 1H, vinylic CH); 5.72–5.57 (m, 1H, vinylic
CH); 5.2–4.75 (m, 5H, two vinylic CH2þCH a to N); 4.45
and 4.24 (two d, AB system, 3JAB¼18 Hz, (1þ1)H); 3.8 (s,
3H); 3.77 (s, 3H); 3.05–2.8 (m, 2H, benzylic CH2); 2.60 (t,
3J¼9 Hz, 1H, CH a to CvO); 2.12–1.90 (broad oct, 1H);
0.80 (d, 3J¼7.0 Hz, 3H); 0.73 (d, 3J¼7.0 Hz, 3H). 13C
NMR: d 174.0; 159.8; 157.5; 137.2; 135.9; 129.45; 129.4;
128.55; 128.3; 128.1; 126.1; 118.5; 117.7; 103.35; 98.05;
59.4; 55.75; 55.35; 55.2; 43.1; 38.75; 30.35; 21.4; 19.85.
HRMS (EI) calcd for C26H33NO3 [Mþ] 407.2460, found
407.2456.
1
dimethoxybenzene 34 (racemic): H NMR (200 MHz): d
3
7.4–7.2 (m, 5H); 7.05 (d, J¼8 Hz, 1H); 6.4–6.3 (m, 2H);
3
6.05–5.85 (m, 1H); 5.2 (d, 1H, Jtrans¼17 Hz); 5.1 (d, 1H,
3Jcis¼10.5 Hz); 4.15 (d, 3J¼7.5 Hz, 1H; 3.8 (s, 3H). 3.75 (s,
3H); 3.65 (s, 2H); 1.95 (broad s, 1H, NH). 13C NMR: d
141.35; 130.54; 128.4; 127.4; 127.05; 114.9; 103.5; 98.5;
65.85; 55.35; 55.3; 46.6.
4.2.3. (2R,10S )-N-(10-Benzyl-prop-20-enyl)-N-[(2,4-
dimethoxyphenyl)methyl]-2-benzyl-but-3-enamide 36a.
646 mL (2.6 mmol) of BSA (N,O-bistrimethylsilylaceta-
mide) were syringed at room temperature into a solution of
733 mg (2.46 mmol) of amine 35 in 2 mL of dichloro-
methane. The reaction was stirred for 1 h at room
temperature before cooling to 08C. A solution of 507.5 mg
(2.6 mmol) of (R )-2-benzyl-but-3-enoyl chloride in 2 mL of
dichloromethane was then added dropwise and the reaction
was stirred for 2 h at 08C and for 16 h at room temperature.
The reaction was quenched with aqueous phosphate buffer
(pH 7). After addition of Et2O, the aqueous phase was
decanted and reextracted with Et2O. The organic phases
were combined, washed with brine, dried over MgSO4.
After evaporation of the solvent, the residue was purified by
column chromatography on silica with heptane/diethyl ether
1:1 to give 921 mg of pure 36a as a pale yellow oil. Yield:
4.2.6. (2R,10R )-N-(10-Benzyl-prop-20-enyl)-N-[(2,4-
dimethoxyphenyl)methyl]-2-isopropyl-but-3-enamide
1
37b. Pale yellow oil. Yield 58%. H NMR (250 MHz): d
7.3–7.15 (m, 5H, benzyl Ar–H); 6.88 (d, J¼8 Hz, 1H, Dmb
Ar–H); 6.45–6.38 (sharp m, 1H, Dmb Ar–H); 6.38–6.32
(dd, J¼8 and 2 Hz, 1H, Dmb Ar–H); 6.0–5.7 (m, 2H, two
vinylic CH); 5.1–4.70 (m, 5H, two vinylic CH2þCH a to
3
N); 4.40 and 4.18 (two d, AB system, JAB¼18 Hz,
(1þ1)H); 3.8 (s, 3H); 3.77 (s, 3H); 3.15–3.02 and 2.95–
1
2
3
82%. [a ]2D0¼254.8 (c 0.90, CHCl3). H NMR (200 MHz,
2.85 (two dd, AB X system, JAB¼14 Hz; JAX¼7.5 Hz;
3JBX¼8 Hz, (1þ1)H); 2.68–2.58 (t, 3J¼9 Hz, 1H, CH a to
CvO); 2.08–1.87 (broad oct, 3J¼7–8 Hz, 1H); 0.90–0.70
(m, 6H).
variable temperature and COSY experiments showed the
presence of two rotamers in a ca. 4:1 ratio): d 7.4–7.0 (m,
10H, benzyl Ar–H); 6.83 (d, J¼8.5 Hz, ca. 0.2H (minor
rotamer), Dmb Ar–H); 6.57 (d, J¼8.5 Hz, ca. 0.8H (major
rotamer), Dmb Ar–H); 6.43 (d, J¼2 Hz, 1H, Dmb Ar–H);
6.36 (dd, J¼8.5 Hz, 2.05 Hz, ca. 0.2H (minor rotamer),
Dmb Ar–H); 6.23 (dd, J¼8.5, 2.0 Hz, ca. 0.8H (major
rotamer), Dmb Ar–H); 5.93–5.58 (m, 2H, two vinylic CH);
5.12–4.70 (m, 5H, two vinylic CH2þCH a to N); 4.30 and
4.13 (two d, AB system, 2JAB¼18 Hz, (1þ1)H); 3.77–3.75
(two s, 6H); 3.35–3.2 (broad q, 1H, CH a to CvO); 3.15–
2.66 (m, 4H, two benzylic CH2); coalescence of the
peaks of the two rotamers was observed at 320 K. 13C
NMR (the presence of the two rotamers induces a
splitting of most peaks; only the peaks of major rotamer
are listed here): d 173.4; 159.8; 157.1; 139.5; 138.1;
136.85; 135.7; 129.4; 129.3; 128.0; 126.05; 125.9; 117.4;
116.5; 103.6; 98.0; 59.2; 55.3; 55.1; 50.2; 42.9; 39.0;
4.2.7. Mixture of (2R p,10S p)- and (2R p,10R p)-N-(10-
phenyl-prop-20-enyl)-N-[2,4-dimethoxyphenyl)methyl]-
2-benzyl-but-3-enamide [38a138b]. Off-white powder.
Yield 82%. NMR spectra are too complex to be of
diagnostic value. HRMS (EI) calcd for C29H31NO3 [Mþ]
441.2304, found 441.2302
4.2.8. Mixture of (2R p,10S p)- and (2R p,10R p)-N-(10-
phenyl-prop-20-enyl)-N-[2,4-dimethoxyphenyl)methyl]-
2-isopropyl-but-3-enamide [39a139b]. Yellow oil. Yield
52%. NMR spectra are too complex to be of diagnostic
value. HRMS (EI) calcd for C25H31NO3 [Mþ] 393.2304,
found 393.2300.
38.5. IR (CHCl3): 1668 (CvO); 1642 (CvC) cm21
.
4.3. General procedure for ring-closing metathesis
HRMS (EI) calcd for C30H33NO3 [Mþ] 455.2460, found
455.2458.
The reaction are run under an argon atmosphere and in
degassed solvent. 7.5 mL of freshly distilled benzene are
syringed in a first Schlenk tube containing 42 mg
(0.05 mmol) of catalyst 41. The resulting solution is then
transfered through a cannula into a second Schlenk tube
containing 0.5 mmol of bis-olefinic amide dissolved in
10 mL of benzene. The reaction mixture is heated under
magnetic stirring at 65–708C for 24–36 h. The reaction
may be conveniently monitored by ccm. After cooling at
room temperature, the solvent is evaporated and the residue
is directly purified by column chromatography on silica with
heptane/AcOEt ca. 7:3 as the eluent.
4.2.4. (2R,10R )-N-(10-Benzyl-prop-20-enyl)-N-[2,4-
dimethoxyphenyl)methyl]-2-benzyl-but-3-enamide 36b.
1
Oil. Yield 80%. H NMR (200 MHz): two rotamers in a
ca. 4:1 ratio: d 7.3–7.1 (m, 10H, benzyl Ar–H); 6.95 (d,
J¼8.5 Hz, ca. 0.2H (minor rotamer), Dmb Ar–H); 6.50 (d,
J¼8.5 Hz, ca. 0.8H (major rotamer), Dmb Ar–H); 6.40 (d,
J¼2 Hz, 1H, Dmb Ar–H); 6.16 (dd, J¼8.5 Hz, 2.5 Hz, ca.
0.8H, (major rotamer), Dmb Ar–H); 6.0–5.75 (m, 2H, two
vinylic CH); 5.18–4.67 (m, 5H, two vinylic CH2þCH a to
2
N); 4.20 and 4.01 (two d, AB system, JAB¼17 Hz,
(1þ1)H); 3.80–3.70 (apparent s, 6H); 3.40–3.15 (broad q,
1H, CH a to CvO); 3.05–2.55 (m, 4H, two benzylic CH2).
HRMS (EI) calcd for C30H33NO3 [Mþ] 455.2460, found
455.2464.
4.3.1. (3R,6S )-N-[(2,4-Dimethoxyphenyl)methyl]-3,6-
dibenzyl-3,6-dihydro-2-pyridone 44a. Oil. Yield 90%.
1
[a ]2D0¼272.8. (c 0.125, CHCl3). H NMR (250 MHz): d

7286
V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
7.33–7.0 (m, 11H, benzyl Ar–Hþ1 Dmb Ar–H); 6.48–
6.40 (m, 2H, Dmb Ar–H); 5.44 (very sharp m, 2H, olefinic
H); 5.34 (d, 2J¼15 Hz, 1H, Dmb CH H); 4.26 (d, 2J¼15 Hz,
1H, Dmb CHH ); 4.03–3.98 (m, 1H, CH a to N); 3.82 (s,
3H); 3.78 (s, 3H); 3.18–3.06 (m, 1H, CH a to CvO); 2.97–
CHH ); 4.09–3.98 (m, 1H, CH a to N); 3.80 (s, 3H); 3.77 (s,
3H); 3.0–2.77 (one m, 1H, CH a to CvO, and two dd, AB X
2
3
3
system, JAB¼ca. 12–13 Hz; JAX¼ca. 4.0 Hz, JBX
¼
7.5 Hz, (1þ1)H); 2.6–2.45 (m, 1H, isopropyl CH); 0.87
3
3
(d, J¼7.0 Hz, 3H); 0.66 (d, J¼7.0 Hz, 3H). 13C NMR: d
170.7; 160.1; 158.45; 136.5; 130.2; 129.9; 128.1; 126.5;
126.2; 124.05; 117.5; 104.3; 98.35; 57.35; 55.3; 45.95; 40.8;
39.7; 28.9; 20.05; 17.6.
2
2.89 and 2.2–2.1 (two dd, AB X system, JAB¼13 Hz,
3
3JAX¼4 Hz, JBX¼8.5 Hz, (1þ1)H); 2.85–2.76 and 2.06–
2
3
1.93 (two dd, AB X system, JAB¼13 Hz, JAX¼3 Hz,
1
3JBX¼9 Hz, (1þ1)H). H NMR (250 MHz, toluene d8): d
7.46 (d, J¼8 Hz) and 7.2–6.97 (m) (10H, Ar–H); 6.88 (d,
1H, J¼10 Hz, Ar–H); 6.38–6.28 (m, 2H, Ar–H); 5.64 (d,
2J¼15 Hz, 1H, Dmb CH H); 5.29–5.1 (two dd, J¼10.5 and
3.9 Hz, 2H, olefinic H); 4.33 (d, 2J¼15 Hz, 1H, Dmb
CHH ); 3.98–3.87 (m, 1H, CH a to N); 3.37 (s, 3H); 3.32 (s,
3H); 3.20–3.08 (m, 1H, CH a to CvO); 2.98–2.82 and
4.3.5. (3R p,6S p)-N-[(2,4-Dimethoxyphenyl)methyl]-3-
benzyl-6-phenyl-3,6-dihydro-2-pyridone 42a. Rf (SiO2,
heptane/AcOEt 7:3): 0.24. Solid. Mp: 828C. Yield 42%
1
(theoretical yield 50%). H NMR (200 MHz): d 7.32–7.16
(m, 9H, Ar–H); 6.68–6.6 (m, 2H, Ar–H); 6.58–6.48 (m,
2H, Ar–H); 5.62–5.50 (sharp m, 2H, olefinic H); 5.10 (d,
2J¼14 Hz, 1H, Dmb CH H); 4.95–4.88 (m, 1H, CH a to N);
2
2.40–2.25 (two dd, AB X system, JAB¼15.0 Hz,
3
2
3JAX¼1.5 Hz, JBX¼5 Hz, (1þ1)H); 2.70–2.56 and 1.90–
3.79 (s, 3H); 3.70 (s, 3H); 3.58 (d, J¼14 Hz, 1H, Dmb
2
3
1.78 (two dd, AB X system, JAB¼13.0 Hz, JAX¼1.5 Hz,
3JBX¼5 Hz, (1þ1)H). 13C NMR: d 170.2; 160.1; 158.4;
138.6; 136.5; 130.7; 129.8; 129.5; 128.1; 128.0; 126.5;
126.2; 124.9; 117.5; 104.3; 98.2; 57.7; 55.24; 55.2; 43.7;
40.5; 39.8; 39.4. GC/MS (EI) 336 (25%, Mþ291); 151
(100%, Mþ2C6H3(MeO)22CH2); 91 (63%). HRMS (EI)
calcd for C28H29NO3 [Mþ] 427.2153, found 427.2147.
CHH ); 3.47–3.35 (m, 1H, CH a to CvO); 3.35–3.12 (two
2
3
3
dd, AB X system, JAB¼13.0 Hz, JAX¼5.0 Hz, JBX¼ca.
7 Hz, (1þ1)H). 13C NMR: d 169.35; 160.1; 158.5; 139.95;
138.3; 131.0; 129.95; 128.55; 128.45; 128.35; 128.3;
127.55; 126.95; 126.4; 126.15; 123.5; 117.45; 104.0;
98.15; 62.35; 55.25; 55.05; 43.0; 41.55; 39.65. HRMS
(EI) calcd for C27H28NO3 [Mþ] 413.1991, found 413.1997.
4.3.2. (3R,6R )-N-[(2,4-Dimethoxyphenyl)methyl]-3,6-
dibenzyl-3,6-dihydro-2-pyridone 44b. Oil. Yield 83%.
1H NMR (250 MHz): d 7.27–7.0 (m, 10H, benzyl Ar–H);
6.86 (d, 1H, J¼8.5 Hz, Dmb ArH); 6.47–6.35 (m, 2H, Dmb
Ar–H); 5.54 (very sharp m, 2H, olefinic H); 5.32 (d,
4.3.6. (3R p,6R p)-N-[(2,4-Dimethoxyphenyl)methyl]-3-
benzyl-6-phenyl-3,6-dihydro-2-pyridone 42b. Rf (SiO2,
heptane/AcOEt 7:3): 0.34. Solid. Mp: 858C. Yield 42%
1
(theoretical yield 50%). H NMR (200 MHz): d 7.38–7.08
(m, 10H, benzyl Ar–H); 6.83 (d, J¼8 Hz, 1H, Dmb Ar–H);
6.41–6.31 (m, 2H, Dmb Ar–H); 5.63–5.56 (sharp m, 2H,
olefinic H); 5.19 (d, 2JAB¼15 Hz, 1H, Dmb CHH); 4.81–4.72
(m, 1H, CH a to N); 3.79 (s, 3H); 3.69 (s, 3H); 3.64 (partially
masked d, 1H, Dmb CHH); 3.55–3.42 (m, 1H, CH a to
CvO); 3.4–3.3 and 3.18–3.06 (two dd, ABX system,
2
2J¼15 Hz, 1H, Dmb CHH); 4.26 (d, 1H, J¼15 Hz, Dmb
CHH ); 4.05–3.85 (m, 1H, CH a to N); 3.81 (s, 3H); 3.79 (s,
2
3H); 3.21–3.13 (dd, part of AB X system, JAB¼14 Hz;
3JAB¼4.5 Hz, 1H); 2.93–2.78 (m, 3H, two benzylic H and
CH a to CvO); 2.46–2.36 (m, 1H, benzylic H). 13C NMR:
d 170.55; 160.0; 158.45; 139.20; 136.2; 130.0; 129.8;
129.55; 128.1; 127.2; 126.55; 126.0; 125.2; 117.45; 104.35;
98.25; 57.8; 55.35; 41.5; 40.8; 39.35; 37.3.
3
3
2JAB¼13.5 Hz, JAX¼4.5 Hz, JBX¼8 Hz, (1þ1)H). 13C
NMR: d 169.75; 160.05; 158.5: 140.6; 138.7; 130.15; 129.7;
128.75; 128.15; 127.82; 126.9: 126.3; 126.15; 124.05; 117.25;
104.1; 98.15; 62.1; 55.35; 55.05; 42.15; 41.45; 38.8. HRMS
(EI) calcd for C27H28NO3 [Mþ] 413.1991, found 413.1993.
4.3.3. (3R,6S )-N-[(2,4-Dimethoxyphenyl)methyl]-3-iso-
propyl-6-benzyl-3,6-dihydro-2-pyridone 45a. Oil. Yield
90%. [a ]2D0¼220.0 (c 1.0, CHCl3). 1H NMR (250 MHz): d
7.30–7.12 (m, 5H, benzyl ArH); 7.07 (d, 1H, J¼6.5 Hz,
Dmb Ar–H); 6.5–6.4 (sharp m, 2H, Dmb Ar–H); 5.68–5.6
4.3.7. Mixture of (3R p,6S p)- and (3R p,6R p)-N-[(2,4-
dimethoxyphenyl)methyl]-3-isopropyl-6-phenyl-3,6-
dihydro-2-pyridone [43a143b]. Oil. Yield 72%. 1H NMR
(250 MHz): d 7.38–7.05 (m, 6Hþ6H, Ar–H); 6.48–6.3 (m,
2Hþ2H, Ar–H); 5.80–5.6 (m, 2Hþ2H, olefinic H); 5.31 (d,
3
(dd, J¼10.5 and 4 Hz, 1H, olefinic H); 5.54–5.47 (dd,
3J¼10.5 and 4 Hz, 1H, olefinic H); 5.28 (d, 2J¼15 Hz, 1H,
2
2
Dmb CH H); 4.34 (d, J¼15 Hz, 1H, Dmb CHH ); 4.08–
2J¼14.5 Hz, 1H, Dmb CH H); 5.18 (d, J¼14.5 Hz, 1H,
3.97 (m, 1H, CH a to N); 3.83 (s, 3H); 3.77 (s, 3H); 3.4–
3.27 and 2.63–2.53 (two dd, AB X system, JAB¼13.0 Hz,
Dmb CHH ); 5.06–4.98 (m, 1H CH a to N); 4.9–4.82 (m,
1H, CH a to N); 3.82–3.68 (four sþone d (?), 13H); 3.55 (d,
2JAB¼14.5 Hz, Dmb CHH ); 3.1–3.02 (m, 1H, CH a to
CvO); 3.0–2.9 (m, 1H, CH a to CvO); 2.80–2.58 (m (two
overlapping oct), 1Hþ1H); 1.06 (d, 3J¼7 Hz, 3H); 1.02 (d,
2
3
3JAX¼4.0 Hz, JBX¼10.0 Hz, (1þ1)H); 2.9–2.8 (m, 1H,
CH a to CvO); 2.30–2.17 (broad oct, 1H); 1.00 (d,
3J¼7.0 Hz, 3H); 0.82 (d, 3J¼7.0 Hz, 3H). 13C NMR: d
170.7; 160.1; 158.45; 137.25; 130.85; 129.41; 129.39;
126.5; 125.95; 123.45; 117.95; 104.35; 98.25; 58.45; 55.35;
55.3; 47.95; 42.05; 40.7; 31.25; 20.6; 18.95. HRMS (EI)
calcd for C24H29NO3 [Mþ] 379.2148, found 379.2152.
3
3
3J¼7 Hz, 3H); 0.95 (d, J¼7 Hz, 3H); 0.75 (d, J¼7 Hz,
3H). 13C NMR: d 170.35; 170.3; 160.20; 160.1; 158.65;
158.6; 140.9; 140.7; 131.05; 130.95; 128.8; 128.7; 127.9;
127.75; 127.6; 127.15; 126.95; 121.30; 121.05; 117.7;
117.5; 104.05; 103.85; 98.7; 98.2; 62.25; 61.8; 55.35; 55.10;
55.05; 46.85; 46.4; 41.85; 41.55; 30.55; 20.6; 20.2; 19.05;
17.55. HRMS (EI) calcd for C23H27NO3 [Mþ] 393.2304,
found 393.2300.
4.3.4. (3R,6R )-N-[(2,4-Dimethoxyphenyl)methyl]-3-iso-
propyl-6-benzyl-3,6-dihydro-2-pyridone 45b. Oil. Yield
80%. [a ]2D0¼278.8 (c 0.78, CHCl3). 1H NMR (250 MHz): d
7.3–7.0 (m, 6H, benzyl Ar–Hþ1 Dmb Ar–H); 6.5–6.4 (m,
2H, Dmb Ar–H); 5.21–5.06 (m, 2H, olefinic H); 5.41 (d,
4.3.8. (3R,6S)-3,6-Dibenzyl-3,6-dihydro-2-pyridone 46a.
155 mg (0.36 mmol) of (3R,6S)-N-[(2,4-dimethoxyphenyl)-
2
2J¼15 Hz, 1H, Dmb CHH); 4.22 (d, J¼15 Hz, 1H, Dmb

V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
7287
methyl]-3,6-dibenzyl-3,6-dihydro-2-pyridone 44a were dis-
solved in 40 mL of trifluoracetic acid (freshly distilled over
a small amount of P2O5) containing 115.5 mL (0.72 mmol)
of triethylsilane. The reaction mixture was heated at reflux
for 30 min and then allowed to cool to room temperature.
Trifluoroacetic acid was removed by rotary evaporation and
the residue was directly purified by column chromatography
on silica using a gradient of heptane/AcOEt from 7:3 to 2:8,
86 mg of 46a were collected as a white solid: Yield: 85%.
3J¼10 Hz, 1H, olefinic H); 5.01–4.97 (m, 1H, CH a to N);
3.36–3.30 (m, 1H, CH a to CvO); 3.27–3.22 and 3.16–
3.10 (two dd, AB X system, JAB¼13 Hz, JAX¼7 Hz,
3JBX¼4 Hz, (1þ1)H). 13C NMR: d 170.3; 140.6; 137.85;
130.05; 128.8; 128.4; 127.95; 126.7; 126.5; 125.3; 124.65;
58.8; 41.65; 38.6. HRMS (EI) calcd for C18H17NO [Mþ]
263.1310, found 263.1305.
2
3
4.3.13. (3R p,6R p)-3-Benzyl-6-phenyl-3,6-dihydro-2-pyr-
1
1
Mp: 120–1238C. [a]D20¼2221 (c 0.2, CHCl3). H NMR
idone. White solid. Yield 85%. Mp: 121–1238C. H NMR
(200 MHz): d 7.40–6.93 (m, 10H, Ar–H); 6.15 (broad s,
1H, NH); 5.7–5.55 (sharp m, 2H, olefinic H); 4.1–3.98 (m,
1H, CH a to N); 3.27–3.13 (m, 1H, CH a to CvO); 3.09–
(400 MHz): d 7.35–7.12 (m, 10H, Ar–H); 5.93 (broad s,
1H, NH); 5.65 (sharp m, 2H, olefinic H); 4.73 (d,
3J¼4.5 Hz, 1H, CH a to N); 3.35–3.30 (m, 1H, CH a to
CvO); 3.27–3.21 and 3.07–3.0 (two dd, ABX system,
2
2.95 and 2.90–2.78 (two dd, AB X system, JAB¼13 Hz,
3
3
3
3JAX¼4 Hz, JBX¼7.5 Hz, (1þ1)H); 2.48–2.35 and 1.90–
2JAB¼13 Hz, JAX¼4 Hz, JBX¼8.5 Hz, (1þ1)H). 13C
NMR: d 171.1; 145.6; 141.1; 138.0; 129.6; 129.0; 128.27;
128.25; 128.23; 126.5; 125.85; 124.8; 58.35; 41.9; 38.8.
HRMS (EI) calcd for C18H17NO [Mþ] 263.1310, found
263.1309.
2
3
1.72 (two dd, ABX system, JAB¼13.5 Hz, JAX¼5 Hz,
3JBX¼8.5 Hz, (1þ1)H). 13C NMR: d 171.3; 137.8; 136.4;
129.9; 129.45; 128.5; 128.1; 126.7; 126.4; 125.6; 124.8;
55.0; 43.7; 43.4; 38.7. IR (CHCl3): 1678 (CvO); 1654
(CvC) cm21. GC/MS (EI) m/z: (rel. int.): 277 [Mþ] (0.5%),
186 (18%), 91 (100%).
4.4. (3R,6S )-3,6-Dibenzyl-2-ethoxy-3,6-dihydropyridine
47
4.3.9. (3R,6R)-3,6-Dibenzyl-3,6-dihydro-2-pyridone. White
1
solid. Yield: 80%. Mp: 102–1038C. H NMR (250 MHz): d
7.35–7.05 (m, 10H, Ar–H); 6.08 (broad s, 1H, NH); 5.70–5.52
100 mg (0.36 mmol)) of (3R,6S)-3,6-dibenzyl-3,6-dihydro-
2-pyridone 46a were introduced into a Schlenk tube and put
in solution into 3 mL of degassed dichloromethane under an
argon atmosphere. A solution of 82.2 mg (0.43 mmol) of
freshly recrystallised (pentane/CH2Cl2) triethyloxonium
tetrafluoroborate in 3 mL of dichloromethane contained in
another Schlenk tube was added through a cannula to the
reaction mixture which gradually turned purple. After
stirring at room temperature for 2 h, the reaction was
quenched by adding 8 equiv. of degassed 1 M aqueous
phosphate buffer (pH 7). The organic phase was transferred
through a cannula into a third Schlenk tube containing
MgSO4. The remaining aqueous phase was extracted by
5 mL of additional degassed CH2Cl2 and the new CH2Cl2
phase was also transferred by a cannula into the third
Schlenk tube. After drying, the joined organic phases were
transferred via a cannula in a fourth Schlenk and the solvent
was evaporated on a vacuum line. The crude imidate which
could be contaminated by ca. 5–10% of starting pyridone
was not stored, but directly engaged in the subsequent
hydrolytic step.
(sharp m (two dd), 2H, olefinic H); 3.98–3.85 (m, 1H, CH a to
2
N); 3.22–3.12 (dd, part of AB X system, JAB¼13 Hz,
3JAX¼4 Hz, 1H); 3.10–3.01 (m, 1H, CH a to CvO); 2.98–
2.80 (m, parts of AB X system, 2H); 2.68–2.5 (dd, part of ABX
system, 2JAB¼13.5 Hz, 3JAX¼8.5 Hz, 1H). 13C NMR: d 171.7;
138.05; 136.15; 129.45; 129.35; 128.7; 128.15; 126.95; 126.3;
125.75; 125.05; 54.55; 43.4; 42.1; 34.5.
4.3.10. (3R,6S )-3-Isopropyl-6-benzyl-3,6-dihydro-2-pyr-
idone. White solid. Yield: 88%. Mp: 102–1048C.
[a]2D0¼238.7 (c 1.26, CHCl3). 1H NMR (250 MHz): d
7.35–7.1 (m, 5H, Ar–H); 6.32 (broad s, 1H, NH); 5.85–
5.72 (broad d, 3J¼10.5 Hz, 1H, olefinic H); 5.70–5.61
3
(broad d, J¼10.5 Hz, 1H, olefinic H); 4.25–4.12 (m, 1H,
CH a to N); 2.98–2.85 and 2.72–2.60 (two dd, AB X
system, JAB¼13 Hz, JAX¼5.5 Hz, JBX¼8.5 Hz, (1þ1)
2
3
3
H); 2.9–2.8 (m, 1H, CH a to CvO); 2.47–2.28 (broad oct,
3
3
1H); 0.99 (d, J¼7 Hz, 3H); 0.77 (d, J¼7 Hz, 3H). 13C
NMR: d 171.7; 136.85; 129.35; 128.95; 127.2; 125.7; 123.2;
55.2; 46.4; 38.75; 27.05; 19.75; 17.3.
4.4.1. (3R,6S )-3,6-Dibenzyl-2-ethoxy-3,6-dihydropyr-
1
4.3.11. (3R,6R )-3-Isopropyl-6-benzyl-3,6-dihydro-2-pyr-
idone. Viscous oil. Yield 85%. [a ]2D0¼247 (c 0.77, CHCl3).
1H NMR (200 MHz): d 7.4–7.1 (m, 5H, Ar–H); 6.75 (broad
s, 1H, NH); 5.9–5.79 (broad d, 3J¼10 Hz, 1H, olefinic H);
idine 47. Oil. H NMR (200 MHz, CD2Cl2): d 7.36–7.0
(m, 10H, Ar–H); 5.71–5.62 (dd, 3J¼10 and 1 Hz, 1H,
3
olefinic H); 5.59–5.48 (dd, J¼10 and 2.5 Hz, 1H, olefinic
H); 4.28–4.0 (m, 3H, ethyl CH2þCH a to N); 3.10–2.95
3
5.79–5.65 (broad d, J¼10 Hz, 1H, olefinic H); 4.3–4.16
(m, 1H, CH a to CvN); 2.85–2.75 (dd, part of AB X
system, JAB¼13 Hz, JAX¼4.5 Hz, 1H); 2.45–2.3 (m
2
3
(m, 1H, CH a to N); 2.99–2.75 and 2.78–2.65 (two dd,
2
3
3
AB X system, JAB¼13.5 Hz, JAX¼5.5 Hz, JBX¼8 Hz,
(1þ1)H); 2.8–2.7 (m, 1H, CH a to CvO); 2.48–2.28 (m,
1H, isopropyl CH); 0.96 (d, 3J¼7 Hz, 3H); 0.79 (d,
3J¼7 Hz, 3H). 13C NMR: d 172.0; 136.2; 129.4; 128.8;
127.1; 125.9; 122.7; 55.9; 46.1; 43.4; 30.9; 19.75; 17.3.
(apparent quint.), parts of AB X system, 2H); 2.18–2.05
2
2
(dd, part of AB X system, JAB¼13 Hz, JAX¼7 Hz, 1H);
3
1.32 (t, J¼7 Hz).
4.4.2. (3R,6R )-3,6-Dibenzyl-2-ethoxy-3,6-dihydropyr-
1
idine. Oil. H NMR (250 MHz, CD2Cl2): d 7.32–7.05 (m,
10H, Ar–H); 5.8–5.7 (broad d, 3J¼11 Hz, 1H, olefinic H);
4.3.12. (3R p,6S p)-3-Benzyl-6-phenyl-3,6-dihydro-2-pyr-
1
3
idone. White solid. Yield 80%. Mp: 119–1208C. H NMR
3
5.65–5.54 (dd, J¼11 and 1 Hz, 1H, olefinic H); 4.4–4.18
(400 MHz): d 7.22–7.17 (m, 8H, Ar–H); 6.61 (dd, J¼7
(m, 2H, ethyl CH2); 4.2–4.08 (m, 1H, CH a to N); 3.12–
2.75 (m, 5H, two benzylic CH2þCH a to CvN); 1.35 (t,
3J¼7 Hz, 3H).
and 1.5 Hz, 2H, Ar–H); 6.07 (broad s, 1H, NH); 5.7–5.64
(dt, J¼10 and 2 Hz, 1H, olefinic H); 5.63–5.57 (broad d,
3

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V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
4.4.3. (3R,6S )-3-Isopropyl-6-benzyl-2-ethoxy-3,6-di-
hydropyridine. Oil. 1H NMR (250 MHz, CD2Cl2): d
7.35–7.18 (m, 5H, Ar–H); 5.87–5.75 (dd, 3J¼10 and
50W-X8 (Hþ form) cation exchange resin. The column was
eluted first with water and then with 1N NH4OH. The
fractions containing the amino acid were combined,
concentrated by rotary evaporation and finally pumped out
on a vacuum line. The residual aminoacid was converted
back to its hydrochloride salt 49a. 107 mg of a white powder
were thus collected. Yield: 85% (based on dihydropyridone
3
1 Hz, 1H, olefinic H); 5.73–5.6 (dd, J¼10 and 2 Hz, 1H,
olefinic H); 4.55–4.48 (m, 1H, CH a to N); 4.48–4.2 (q,
3J¼7 Hz, 2H, ethyl CH2); 3.2–3.05 and 2.88–2.73 (two dd,
AB X system, 2JAB¼13 Hz, 3JAX¼8 Hz, 3JBX¼8 Hz, (1þ1)
H); ca. 2.85 (m, partially masked, 1H, CH a to CvN);
2.18–2.0 (m, 1H); 1.35 (t, 3J¼7 Hz, 3H); 0.95 (d, 3J¼7 Hz,
1
46a, three steps). [a ]2D0¼269.3 (c 0.07, H2O). H NMR
(200 MHz, D2O): d 7.2–6.8 (m, 10H, Ar–H); 5.55 (t,
3J¼11.5 Hz, 1H, olefinic H); 5.30 (t, 3J¼10.6 Hz, 1H,
3
3H); 0.63 (d, J¼7 Hz, 3H).
3
olefinic H); 4.0 (broad q, J¼9 Hz, 1H, CH a to N); 3.22
4.4.4. (3R,6R )-3-Isopropyl-6-benzyl-2-ethoxy-3,6-di-
1
(broad q, 3J¼9 Hz, 1H, CH a to CvO); 2.62–2.40 (m, 2H,
hydropyridine. H NMR (250 MHz, CD2Cl2): d 7.4–7.18
3
parts of AB X sysems); 2.20–2.06 (dd, part of AB X system,
3
(m, 5H); 6.0–5.92 (broad d, J¼10 Hz, 1H, olefinic H);
2JAB¼13.5 Hz, JAX¼8 Hz, 1H); 2.05–1.92 (dd, part of
5.76–5.65 (m, 1H, olefinic H); 4.86–4.75 (m, 1H, CH a to
N); 4.68–4.47 (m, 2H, ethyl CH2); 3.34–3.26 and 3.14–
ABX system, 2JAB¼13.5 Hz, 3JAX¼6.0 Hz, 1H). 13C NMR
(D2O): d 177.0; 134.9; 133.1; 129.6; 129.1; 128.9; 128.5;
127.4; 126.6; 49.8; 46.4; 38.5; 37.4. Anal. Calcd for
C19H22NO2Cl. 2.2 H2O: C, 61.47; H, 7.16; N, 3.77.
Found: C, 61.47; H, 7.05; N, 3.76.
2
3
3.04 (two dd, AB X system, JAB¼13.5 Hz, JAX¼4 Hz,
3JBX¼8 Hz, (1þ1)H); 2.75–2.62 (m, 1H, CH a to CvN);
3
2.40–2.30 (m, 1H, isopropyl CH); 1.54 (t, J¼7 Hz, 3H);
3
3
0.98 (d, J¼7 Hz, 3H); 0.86 (d, J¼7 Hz, 3H).
(2R,5S )-2-benzyl-5-amino-6-phenyl-3-hexenoic acid:
HRMS (ESI negative mode): calcd for C19H21NO2
[M2H]2 294.1494, found 294.1490.
4.4.5. (3R p,6S p)-3-Benzyl-6-phenyl-2-ethoxy-3,6-di-
1
hydropyridine. H NMR (200 MHz, CD2Cl2): d 7.3–7.11
(m, 8H, Ar–H); 6.68–6.52 (m, 2H, Ar–H); 5.78–5.6 (m,
2H, olefinic H); 5.15–5.05 (broad d, J¼ca. 6.5 Hz, 1H, CH
a to N); 4.15 (q, 3J¼7 Hz, 2H, ethyl CH2); 3.28–3.0 (m, 3H,
Others pseudopeptidic analogs were obtained in a similar
way. They were characterised by high resolution mass
spectroscopy on the zwitterion and NMR spectroscopy on
the hydrochloride salt.
3
benzylic CH2þCH a to CvN); 1.32 (t, J¼7 Hz, 3H).
4.4.6. (3R p,6R p)-3-Benzyl-6-phenyl-2-ethoxy-3,6-di-
hydropyridine. 1H NMR (200 MHz, CD2Cl2): d 7.27–
7.02 (m, 10H, Ar–H); 5.78–5.55 (m, 2H, olefinic H); 4.70–
4.64 (m, 1H, CH a to N); 4.1–3.97 (q, 3J¼7 Hz, 2H, ethyl
CH2); 3.25–2.8 (m, 3H, benzylic CH2þCH a to CvN);
4.4.8. Ethyl (2R,5R )-2-benzyl-5-amino-6-phenyl-3-hex-
enoate hydrochloride. White powder. 1H NMR (200 MHz,
D2O): d 7.2–6.85 (m, 10H, Ar–H); 5.58–5.48 (t,
3
3J¼11 Hz, 1H, olefinic H); 5.38–5.25 (t, J¼10 Hz, 1H,
3
1.23 (t, J¼7 Hz, 3H).
olefinic H); 3.88–3.7 (m, 1H, CH a to N); 3.7–3.52 (q,
3J¼7 Hz, 2H, ethyl CH2); 3.0–2.45 (m, 5H, two benzylic
3
4.4.7. Ethyl (2R,5S )-2-benzyl-5-amino-6-phenyl-3-hex-
enoate hydrochloride 48 and (2R,5S )-2-benzyl-5-amino-
6-phenyl-3-hexenoic acid hydrochloride 49a. To the
crude imidate 47 (0.36 mmol) contained in a Schlenk tube
under an argon atmosphere was added 0.75 mL of EtOH. To
this ethanolic solution were added 5 mL of aqueous 0.3N
HCl. The reaction mixture which was first cloudy and then
after a while limpid again was stirred under an argon
atmosphere and at room temperature for 24 h. After
extraction with Et2O (for the elimination of the small
amount of dihydropyridone 46a possibly present in starting
crude imidate), the aqueous phase was evaporated under
vacuum to give a white powder which could be identified by
NMR as the amino ester hydrochloride 48. 1H NMR
(200 MHz, D2O): d 7.2–6.7 (m, 10H, Ar–H); 5.6–5.4 (m,
1H, olefinic H); 5.42–5.22 (m, 1H, olefinic H); 4.08–3.9
(broad q, 1H, CH a to N); 3.88–3.72 (q, J¼7.0 Hz, 2H,
ethyl CH2); 3.22–3.05 (m, 1H, CH a to CvO); 2.75–2.58
(dd, part of AB X system, 2JAB¼ca. 13 Hz, 3JAX¼ca. 4.5 Hz,
1H); 2.4–2.1 (m, parts of AB X system, 2H); 1.86–1.7 (dd,
CH2þCH a to CvO); 0.84 (t, J¼7 Hz, 3H).
4.4.9. (2R,5R )-2-Benzyl-5-amino-6-phenyl-3-hexenoic
acid hydrochloride 49b. White powder. Yield based on
dihydropyridone (three steps): 84%; [a ]2D0¼2245 (c 0.22,
1
H2O). H NMR (200 MHz, D2O): d 7.15–6.90 (m, 10H);
3
3
5.48 (t, J¼10.5 Hz, 1H, olefinic H); 5.20 (t, J¼10.5 Hz,
1H, olefinic H); 3.95–3.88 (broad q, 3J¼8 Hz, 1H, CH a to
N); 3.20–3.05 (broad q, 3J¼8 Hz, 1H, CH a to CvO); 2.5–
2.38 (m, 3H, parts of AB X system); 2.18–2.05 (dd, part
2
3
of AB X system, JAB¼14.5 Hz, JAX¼8.0 Hz, 1H). 13C
NMR (D2O): d 176.4; 135.23; 132.85; 129.95; 129.75;
129.5; 129.2; 128.9; 127.7; 127.25; 126.65; 50.7; 46.05;
39.0; 38.5.
(2R,5R )-2-benzyl-5-amino-6-phenyl-3-hexenoic acid:
HRMS (ESI negative mode): calcd for C19H21NO2
[M2H]2 294.1494, found 294.1492.
4.4.10. Ethyl (2R,5S )-2-isopropyl-5-amino-6-phenyl-3-
hexenoate hydrochloride. White powder. 1H NMR
(250 MHz, D2O): d 7.18–6.92 (m, 5H, Ar–H); 5.75–5.68
2
3
part of AB X system, JAB¼ca. 13 Hz, JAX¼ca. 5.5 Hz,
3
1H); 0.88 (t, J¼7 Hz, 3H).
3
(dd, J¼11 Hz and ca. 1–2 Hz, 1H, olefinic H); 5.58–5.48
The above amino ester hydrochloride salt was taken up in
4 mL of 20% aqueous HCl and the solution was heated at
reflux for 2 h. Once cooled to room temperature, the
solution was evaporated under vacuum. The residue was
dissolved in water and loaded onto a column of Dowex
(dd, 3J¼11 Hz and ca. 2 Hz, 1H, olefinic H); 4.55–4.42 (m,
3
1H, CH a to N); 4.27–4.1 (q, J¼7 Hz, 2H, ethyl CH2);
3.0–2.8 (m, 3H, benzylic CH2þCH a to CvO); 1.70–1.57
3
3
(oct, J¼ca. 7 Hz, 1H); 1.18 (t, J¼7 Hz, 3H); 0.62 (d,
3J¼7 Hz, 3H); 0.22 (d, J¼7 Hz, 3H).
3

V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
7289
4.4.11. (2R,5S )-2-Isopropyl-5-amino-6-phenyl-3-hex-
enoic acid hydrochloride 50a. Yield based on dihydro-
pyridone (three steps): 75%. [a ]2D0¼213.3 (c 0.33, H2O).
1H NMR (250 MHz, D2O): d 7.15–6.97 (m, 5H, Ar–H);
and 2.79–2.65 (two dd, ABX system, JAB¼13 Hz,
3
JAX¼6.5 Hz, JBX¼8 Hz, (1þ1)H); 0.68 (t, J¼Hz).
4.4.16. (2R p,5R p)-2-Benzyl-5-amino-5-phenyl-3-penten-
oic acid hydrochloride 51b. White powder. Yield based on
3
3
5.55 (t, J¼10 Hz, 1H, olefinic H); 5.44 (t, J¼10 Hz, 1H,
olefinic H); 4.20–4.05 (broad q, 1H, CH a to N); 2.95–2.6
(m, 3H, benzylic CH2þCH a to CvO); 1.48–1.3 (oct,
1
dihydropyridone (three steps): 80%. H NMR (250 MHz,
D2O): d 7.21–7.0 (m, 10H); 5.9–5.6 (m, 2H, olefinic H);
3
3
3
3J¼7 Hz, 1H); 0.46 (d, J¼7 Hz, 3H); 0.23 (d, J¼7 Hz,
3H). 13C NMR (D2O): d 177.2; 134.5; 130.5; 129.2; 127.5;
126.7; 125.9; 55.1; 48.6; 44.0; 29.8; 18.5; 16.45.
3.48–3.32 (q, J¼8.5 Hz, 1H, CH a to CvO); 3.02–2.88
and 2.82–2.7 (two dd, AB X system, JAB¼13.5 Hz,
JAX¼6.5 Hz, JBX¼8 Hz, (1þ1)H); CH a to N probably
masked by water band. 13C NMR (D2O): d 177.0; 134.75;
132.1; 131.95; 131.85; 131.45; 130.64; 130.45; 130.15;
130.07; 129.7; 54.95; 49.15; 40.5.
(2R,5S )-2-Isopropyl-5-amino-6-phenyl-3-hexenoic acid:
HRMS electrospray: calcd for C15H21NO2 [M2H]2
246.1494, found 246.1495.
(2R p,5R p)-2-Benzyl-5-amino-5-phenyl-3-pentenoic acid:
HRMS (ESI negative mode): calcd for C19H21NO2
[M2H]2 280.1337; found 280.1333.
4.4.12. Ethyl (2R,5R)-2-isopropyl-5-amino-6-phenyl-3-
hexenoate hydrochloride. White powder. (2R,5R)-2-iso-
propyl-5-amino-6-phenyl-3-hexenoic acid hydrochloride
50b: White powder. Yield based on dihydropyridone
1
(three steps): 77%. [a]2D0¼þ25.7 (c 0.17, H2O). H NMR
Acknowledgments
(250 MHz, D2O): d 7.15–6.95 (m, 5H, ArH); 5.60–5.40 (m,
2H, olefinic H); 4.12–4.40 (broad q, 3J¼8 Hz, 1H, CH a to
N); 3.3–2.8 (m, 3H, two benzylic HþCH a to CvO);
1.40–1.27 (oct, 3J¼7 Hz, 1H); 0.48 (d, 3J¼7 Hz, 3H); 0.28
The contribution of Ms C. Aroulanda and Dr Denis Merlet
from the ‘Laboratoire de Chimie Structurale Organique’
´
(Universite Paris-Sud, Orsay) whose NMR studies in
3
(d, J¼7 Hz, 3H). 13C NMR (D2O): d 177.0; 135.2; 129.5;
anisotropic medium have rendered possible structure
assignments to diastereoisomeric 2,6-disubstituted dihydro-
pyridones (see foot-note §) is gratefully acknowledged. We
thank Dr C. Kouklovsky for very helpful discussions.
127.9; 127.7; 126.5; 124.3; 55.7; 48.7; 43.1; 29.7; 18.5;
16.8.
(2R,5R )-2-Isopropyl-5-amino-6-phenyl-3-hexenoic acid:
HRMS electrospray: calcd for C15H21NO2 [M2H]2
246.1494, found: 246.1492.
References
4.4.13. Ethyl (2R p,5S p)-2-benzyl-5-amino-5-phenyl-3-
pentenoate hydrochloride. White powder. 1H NMR
(250 MHz, D2O): d 7.2–7.08; 6.93–6.78; 6.78–6.68
(three m, 10H, Ar–H); 5.73–5.54 (m (apparent.quint.);
2H, olefinic H); 4.84 (d, 3J¼8.5 Hz, 1 Hz, CH a to N); 3.9–
3.8 (q, 3J¼7 Hz, 2H, ethyl CH2); 3.52–3.4 (broad q, 3J¼ca.
6.5 Hz, 1H, CH a to CvO): 2.78–2.68 and 2.42–2.3 (two
1. Reviews on pseudopeptides: (a) Spatola, A. Chemistry and
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2
3
3
dd, ABX system, JAB¼14 Hz, JAX¼7 Hz, JBX¼8.5 Hz,
3
(1þ1)H); 0.90 (t, J¼7 Hz).
4.4.14. (2R p,5S p)-2-Benzyl-5-amino-5-phenyl-3-pente-
noic acid hydrochloride 51a. White powder. Yield based
on dihydropyridone (three steps): 85%. 1H NMR (250 MHz,
D2O): 7.28–7.03; 7.0–6.85; 6.85–6.78 (three m, 10H, Ar–
H); 5.78–5.58 (m (apparent.quint.), 2H, olefinic H); 4.92 (d,
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3
3J¼8 Hz, 1H, CH a to N); 3.58–3.46 (broad q, J¼ca. 7–
8 Hz, 1H, CH a to CvO); 2.90–2.77 and 2.52–2.4 (two dd,
2
3
3
AB X system, JAB¼13 Hz, JAX¼5 Hz, JBX¼8 Hz,
(1þ1)H). 13C NMR (D2O): d 177.2; 133.8; 132.3; 131.8;
131.35; 131.1; 130.8; 130.5; 130.1; 129.5; 129.2; 55.0;
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6. (a) Galat, A.; Riviere, S. Peptidyl-Prolyl cis/trans Isomerases.
(2R p,5S p)-2-Benzyl-5-amino-5-phenyl-3-pentenoic acid:
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[M2H]2 280.1337, found 280.1340.
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¨
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3
(m, 2H, olefinic H); 4.80 (d, J¼8 Hz, 1H, CH a to N);
3.62–3.38 (m, 3H, ethyl CH2þCH a to CvO); 2.95–2.80

7290
V. Boucard et al. / Tetrahedron 58 (2002) 7275–7290
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